Monday, December 5, 2011

Amyotrophic lateral sclerosis

INTRODUCTION TO AMYOTROPIC LATERAL SCLEROSIS
During the summer of 2011, I read the novel, Tuesday’s with Morrie, by Mitch Albom.  The novel is about the life of retired sociology professor, Morrie Schwartz and his battle with the motor neuron disease, Amyotrophic lateral sclerosis (ALS).  The novel really sparked my interest in this devastating disease and I had the desire to learn more about the symptoms, cause, and treatment of ALS. 
            Amyotrophic lateral sclerosis is also known as Lou Gehrig's disease after New York Yankee first baseman, Lou Gehrig, who was diagnosed with the disease in 1939.  Affecting about 3 in every 100,000 people, ALS is a terrifying chronic, fatal neurodegenerative disease that leaves the individuals mind intact, while causing total paralysis of the body.  Essentially, people with the disease lose all ability to move, but their cognition remains the same, so they are trapped within their own body.  “Amyotrophic” refers to the atrophy, weakness, and fasciculation that signify disease of the lower motor neurons.  “Lateral sclerosis” refers to the hardness that occurs on the lateral columns of the spinal cord in individuals with ALS (Festoff, 2001).   
            Although there is no specific diagnostic test, the clinical diagnosis is correct in more than ninety-five percent of cases.  However, with the lack of an actual test it can sometimes be difficult to distinguish ALS from other motor neuron diseases such as Kennedy’s disease and X-linked spinobulbar muscular atrophy (Rowland, 2011).
The disease progression and symptom emergence varies from person to person, however, eventually most patients are unable to stand, walk, get out of bed, or use their arms and legs.  People with ALS lose their ability to chew and swallow, making them unable to eat easily and increasing the likelihood of choking or aspiration of food and liquids.   Pneumonia and the ability to maintain a healthy body weight become life threatening problems.  Respiratory problems arise when the intercostal muscles of the ribs cage become weak and adequate diaphragm contraction is prohibited.  Without diaphragm contraction, it is impossible to inhale the capability to breathe is lost.  Usually there is no loss in the individual’s ability to see, taste, hear, feel, or blink.  Bladder and bowel control is typically preserved also, however with the inability to walk and move, most people require catheters for excretion.  Throughout the entire progression, the individual does not lose cognitive function and are aware of their condition, which often results in anxiety and depression.  The prognosis of the disease is grim and individuals usually only live for three to five years after they are diagnosed with ALS (Festoff, 2001).

POTENTIAL CAUSES           
                Although the origin of ALS is still not completely understood, scientists and physicians do have several theories on what may cause the disease.  Heritable diseases are the only motor neuron diseases whose causes are known, with five to ten percent of ALS cases being familial, the rest are sporadic.  In twenty percent of familial ALS, the there are mutations on the gene that make the superoxide dismutase (SOD1) enzyme.  SOD1 is an antioxidant that protects the body from damage from the superoxide, a free radical made by the mitochondria and when they accumulate, can damage mitochondrial and nuclear DNA as well as proteins (Deng, 1993).
There are also several environmental causes that have links to ALS.  First, the exposure to heavy metals may contribute to its progression.  Lead intoxication has been attributed to cases of both upper and lower neuron syndromes; however, there have been no convincing reports of lead-induced motor neuron diseases in the last thirty years.
Viral infection is a second possible cause of sporadic ALS.  Enterovirus RNA was detected in the spinal cords of patients with ALS, however the role of enteroviruses, including the polio virus have not yet been established, making it difficult link the cause of ALS to the virus.  Motor neuron disease has also been reported in individuals infected with the human immunodeficiency virus (HIV) or in human T-cell lymphotropic virus type I, but the existence has been so low that it cannot prove that retroviral infection causes motor neuron disease (Ido, 2011)
Besides familial links, environmental factors, and viruses, scientists have some additional theories on the cause of ALS. Autoimmunity may play a role in the disease’s pathogenesis.  Activated microglia and T cells have been present in the spinal cords of patients with ALS who have IgG antibodies against motor neurons.  In patients with sporadic ALS, antibodies against voltage-gated calcium channels may cause interference with the intercellular calcium regulation, which may lead to the degradation of motor neurons.  Immunotherapy has not been effective for patients with ALS, making the idea of an autoimmune cause of ALS controversial because if the cause of ALS is autoimmunity, then immunotherapy should work as a cure (Rowland, 2001).   

PATHOGENESIS
            Although the exact molecular pathways are that cause motor neuron death in ALS patients is still unknown, there are several possible primary mechanisms including the toxic effects of mutated SOD1, including abnormal protein aggregation, the disorganization of intermediate filaments, and glutamate-mediated excitotoxicity (Rowland, 2001).
            Clinically, sporadic ALS and familial ALS are pathologically similar, suggesting they have a common cause.  The SOD1mutation is only found in about two percent of patients with ALS, but the discovery of this mutation was extremely important because it was the first molecular link to the cause of the disease.  In order to catalyze the conversion of toxic superoxide radicals to hydrogen peroxide and oxygen, SOD1 needs a copper atom at the active site to mediate catalysis.  SOD1 also has pre-oxidant activities, including peroxidation, the generation of hydroxyl radicals and the nitration of tyrosine.  Impairment of the antioxidant functions of associated with mutations of SOD1 could lead to the toxic accumulation of superoxide, resulting in a possible molecular mechanism of ALS (Deng, 1993).
            A mutation in SOD1 could also alter the enzyme in a way that enhances its reactivity with abnormal substrates.  For example, if the radical peroxynitrate is used as a substrate of SOD1, abnormal tyrosine nitration could damage proteins.  In patients with ALS, free nitrotyrosine levels in the spinal cord are elevated (Deng, 1993).   
            Oxidative damage may occur when mutations in SOD1 impair the ability of the enzyme to bind to zinc.  When deprived of zinc, SOD1 is less efficient at using superoxide, and the rate of tyrosine nitration increases.  Mutations in SOD1 decrease the enzyme’s affinity for zinc, making the protein more likely to assume a toxic, zinc deficient state.  Zinc-deficient SOD1 still requires copper at the active site even though its activity is irregular.  Chelators (binding agents that suppress chemical activity by creating a ring shaped chemical compound called a chelate which contains a metal ion attached by coordinate bonds to at least two nonmetal ions) remove copper from zinc-deficient SOD1 but not from normal SOD1.  The chelators protected cultured motor neurons from zinc-deficient SOD1, and eventually this discovery may be beneficial in finding a treatment for ALS (Deng, 1993).   
            Possible targets of the SOD1-induced toxicity described earlier include neurofilament proteins composed of heavy, medium, and light subunits.  These subunits are important in determining the shape of cells and in axonal transport.  Large-caliber, neurofilament –rich motor neurons are affected in individuals with ALS and the amount of neurofilaments may be important in selective neuronal vulnerability.  In patients with ALS, neurofilaments accumulate in the cells and proximal axons of motor neurons, and with the accumulation, the neurofilaments become disorganized which could impede the axonal transport of molecules necessary for the maintenance of axons resulting in axonal strangulation and degeneration of motor neurons (Rowland, 2001).
This abnormal amount of neurofilaments may be a result of SOD1 mutation. In mice with SOD1 mutations, expression of the light subunit neurofilaments was eliminated, resulting in the overexpression of heavy subunits ameliorating motor neuron disease.  However, this overexpression of heavy subunits has not yet been observed in humans, so it is unknown if the abnormal amounts of neurofilaments is the cause of ALS, or a byproduct of the disease (Rowland, 2001).  
            Calcium homeostasis and excitotoxicity is another molecular model that may explain the cause of ALS.  There has been evidence that indicates ALS involves a derangement of intracellular free calcium.   Cell death is triggered when abnormal calcium homeostasis activates a chain of several events.  In both human ALS patients and mice with mutant SOD1, the resistance to the degeneration of certain motor neurons such as the oculomotor neurons, may be related to calcium-binding proteins protecting against the toxic effects of high intracellular calcium levels (Festoff, 2001).  
            When excitotoxic injury of neurons occurs, there is excessive entry of extracellular calcium through inappropriate activation of glutamate receptors.  The main excitatory neurotransmitter in the central nervous system is glutamate.  Glutamate works through two different types of receptors: the G protein-coupled receptor, which upon activation, leads to the release of intracellular calcium stores, and the glutamate-gated ion channels, which are characterized by their sensitivity to N-methyl-D-aspartic acid (NMDA) (Festoff, 2001). 
            The NMDA-receptor channel can be permeated by calcium, but the permeability of the non-NMDA0receptor channel is dependent upon the composition of the receptor.  If the subunit GluR2 is present, the channel is impermeable to calcium, however if AMPA receptors, which lack GluR2, are present, the channel can be permeated by calcium.   Motor neurons have selective vulnerability to AMPA.  This vulnerability could be explained because GluR2 expression in motor neurons is lower than in other neurons, or by an editing impairment of GluR2 mRNA in patients with ALS.  Either situation would lead to the expression of calcium-permeable AMPA receptors (Festoff, 2001)  
            Because increased level of glutamate is found in the cerebrospinal fluid of ALS patients, the possibility of glutamate excitotoxicity was suggested.  High levels of glutamate could cause excitotoxicity, which would result in increased amounts of free calcium through the activation of calcium-permeable receptors and voltage-gated calcium channels.  The increased glutamate level could also be from impaired glutamate transport in the central nervous system, however this theory is still not understood and more research must be done on humans (Festoff, 2001).   
            A last molecular mechanism for the explanation of ALS is apoptosis.  There are many ALS triggers that could perturb cellular functions that are essential for the survival of motor neurons.  Motor neurons probably die as a result of apoptosis in SOD1-mediated ALS. However, this idea is highly disputed.  Caspase protease activation in response to Bcl-2 proteins must occur in order for apoptosis to occur.  In mice with SOD1 mutations, the expression of Bcl-2 delayed the start of motor neuron disease and prolonged life.  Interleukin-1β-converting enzyme (a caspase inhibitor) also slowed ALS progression.  Although apoptosis is one of the later events motor neuron degeneration, it may be one of the causes of ALS (Rowland, 2001)   



CURRENT TREATMENT
            The glutamate antagonist drug, riluzole, is the only FDA approved medication for the treatment of ALS, and in two therapeutic trials, it prolonged life by three to six months.  In one of the trials, it also slowed the loss of limb function, but only slightly.  The success of the drug has been taken as evidence in support of the excitotoxic-glutamate theory of pathogenesis for ALS.  Other glutamate antagonists have not proven to be beneficial though, and there are no other drugs that have been found to decrease the progression of the disease or increase lifespan (Festoff, 2001).
            Since there are is no cure for ALS, efforts and treatments to make an ALS patient more comfortable and improve quality of life are taken.  Mechanical ventilator support is a huge decision patients must face and they must make the decision to undergo a tracheostomy for long-term mechanical ventilation must be made.   The need for a tracheostomy can be postponed, however, if the individual chooses to use a noninvasive positive pressure ventilation system commonly called BiPAP.  BiPAP forces oxygen into the person’s lungs by the use of positive pressure.  Very few patients opt to undergo a tracheostomy as it inhibits movement and the ability to communicate (Rowland, 2001). 
            Because ALS is such a terrifying and debilitating disease, most patients become severely depressed.  Antidepressants are often prescribed to help boost the patient’s morale in their final years of life.  Some people do not like to take antidepressants and often find psychological and spiritual help to be more effective methods to control depression (Festoff, 2001).
CONCLUSION
            Amyotrophic lateral sclerosis is a horrifying, painful disease that is always fatal.  Currently, there is only one medication used to prolong life by only a mere three to six months. An individual with ALS is completely aware that they are facing a terrible death where their mind will remain intact while their body quickly betrays them.  More research on the cause of this neurodegenerative disease must be done before a treatment can be found and hopefully stop the progression of the disease before the individual becomes a prisoner in their own body and dies a dreadful death.  

Kill one to save five? An update

Earlier in my blogging I discussed a moral dilemma that psychologists and neurobiologists have been talking about for years.  The question was would you flip a switch to re-route a train to kill only one person instead or five? And the article also asked if you would push someone in front of a train to stop it from killing five?  In both situations there is a way to save either one person or save five people.  When given the option to simply flip a switch, most people will opt to flip the switch to save five, the obvious choice. However, most people say they would be unable to actually push someone to their death to save five because of the emotional and moral issues associated with physically causing someone else's death.

Many scientists have argued that this is too unrealistic to expect someone to make the decision in such a hypothetical situation.  So, in an article in Emotion, researchers created a 3-D virtual environment and tested the actions of 147 people.  The people felt like they were actually in the situation and researchers hoped this would provide a more realistic test.  Unsurprisingly, when it came to simply flipping a switch, majority of people saved five instead of one by re-routing the train.  When it came to pushing someone, most people were still unable to push someone to their death even though they were able to see a train barreling at the five other people.

This is such an interesting dilemma, and it is even more interesting when the situation is actually more realistic (even though nobody actually died).  On paper it seems like such an obvious option to save five people over one, but I honestly don't think that I would be able to physically push someone to their death.   

Saturday, November 26, 2011

The importance of music

There is no escaping it… music is everywhere you go. Whether you are in your car, at the store, at work, or even in an elevator, there never seems to be a quiet moment without some sort of melody surrounding you, especially right now with the holiday season approaching.  I thoroughly enjoy music and currently have it playing as I sit here writing this blog entry.  In their paper, Music and emotions in the brain: familiarity matters, Carlos Silva Pereira and colleagues address the question: is the appreciation of music based on familiarity? Basically, they wanted to know if a person enjoys a song more if they have heard it, and are familiar with it. 
                To do this, they used fMRI to see the brain’s reaction when an individual listens to music they have heard before and music they are unfamiliar with.  They found that musical preferences, such as favoring rock music over country music had very little effect on the activation of the limbic, paralimbic, and reward system areas.  However, familiarity with a song triggered an increases blood oxygen level dependence response in the amygdala, nucleus accumbens, anterior cingulate cortex and thalamus. So, because of the areas activated when familiar music is played it can be concluded that the brain is more responsive to familiar music.
                I think this is very interesting because it makes me wonder if familiar music could be used in the healing and recovery process of people with traumatic brain injuries. Maybe it would be beneficial in creating more brain action in someone with an injury, therefore resulting in a faster healing time.  It also makes me wonder if familiar music should be played for people with progressive brain diseases such as Alzheimer’s because the increased brain activity could help to keep the individuals mind sharper and slow the process of memory loss.    

A historical survey of the contributions of Santiago Ramon y Cajal, Carl Speidel, and Ross Harrison in the field of neuroscience


            There are many names in the growing and increasingly popular field of neuroscience. Everyday new discoveries are made and we come closer to unlocking the mystery of the human mind.  Three men stand out in the field, and have made huge contributions to understanding the brain.  Santiago Ramon y Cajal, Ross Harrison, and Carl Speidel have, throughout different time periods, increased the knowledge of growth cones and many other concepts on the subject of the development of the nervous system (Sanes, 2012). 
            According to Rodulfo R. Llinás, professor of neuroscience and chairman of the department of physiology and neuroscience at New York University School of Medicine, Santiago Ramon y Cajal is arguably “the most accomplished anatomist in the history of neuroscience” (Llinás, 2003.)  Cajal was a Spanish physician and scientist and is considered by many to be the founder of modern neurobiology. He was awarded, along with Camillo Golgi, the Nobel Prize in Physiology or Medicine (de Castro et al, 2007).
Using Golgi’s technique of staining, with several of his own alterations, Cajal was the first to report, with precision, the fine anatomy of the nervous system and he was able to demonstrate that the nervous system was made up of individual neurons interconnected by small contact zones; these contact zones were termed synapses by Charles Scott Sherrington.  His work was documented in the neuron doctrine, and although Cajal used Golgi’s staining technique, Golgi did not agree with Cajal’s work in the neuron doctrine, and instead favored the work done in the previous study, the reticular theory.  Much tension arose when the two men received the shared Nobel Prize 1906, being as both disagreed with each other’s works (de Castro et al, 2007).
            Cajal’s studies were always presented in a functional context and one of his most insightful hypotheses was that neurons were functionally polarized (Llinás, 2003).  This idea meant that electrical impulses propagate from dendrites to the cell body and finally to the axon.  He also speculated that neurons were units with the function of information processing that make connections and organize energetic networks to accomplish their functions; a speculation that is now accepted as correct (de Castro et al, 2007).
            In 1890, Cajal observed an amoeboid-like structure at the end of the axon of developing nerve cells.  Seeing pictures of static images of fixed he reasoned that the end of the axon must me mobile and that the axon must be involved in the growth and targeting that is necessary for an axon to connect with other neurons.  He called this structure the axon’s growth cone (de Castro et al, 2007).
            Several years after Cajal’s work with growth cones, American embryologist Ross Granville Harrison developed a way to view live tissue under a microscope using culture techniques.  After receiving his bachelor’s degree in 1889 from Johns Hopkins University at the age of nineteen, Harrison worked as a laboratory assistant for the United States Fish Commission where he studied the embryology of the oyster.  He became an M.D. and received his Ph.D , and began teaching histology and embryology until 1907 at Johns Hopkins University.  By this time, his work with tissue culturing became influential and was of interest to many leading biologists of the time (Nicholas, 1961). 
            After 1907, he began teaching comparative anatomy at Yale University where he was able to successfully culture frog neuroblasts  by placing segments of the embryonic neural tube into a lymph medium.  After placing these segments into the medium, he was able to see live growth cones moving across the microscope slide, and he could view the growth cones changing their form (Nicholas, 1961).   With this achievement, he was able to describe in incredible detail the activities of growth cones and their role in creating new nerve fibers (Speidel, 1942).  With his knowledge on growth cones, he began the current research on precursor and stem cells. His work with the growth cone has helped shape the modern understanding of how the nervous system functions and has also helped develop techniques for surgical tissue transplant techniques (Nicholas, 1961). 
            Armed with Cajal’s picture on stained material of changes in nerve cells and endings through generation and regeneration and Harrison’s work with live culturing, Carl Speidel was able to begin his own research on growth cones.  Speidel watched individual nerve fibers for prolonged periods of time in living tadpoles.  He was able to obtain the entire history of a single nerve fiber for several days to weeks, revealing minute details of the nerve fiber changes.  He was able to see the extension and retractions at the tips of young or rapidly regenerating nerve fibers, and realized that at the early stage of development of the living frog tadpole, nerve fibers could be watched as they grew out towards the skin.  Finding that mobile growth cones are present at the tips of the nerve fiber, Speidel discovered that they grow in a sporadic fashion with great variation.  Second and later growth cones then follow the path laid down by the primary growth cone and a small nerve is then formed.  Speidel found it amazing at the ability of the growth cones to re-route in different directions if obstacles were present and at their ability to respond to injury (Speidel, 1942). 
            Ramon y Cajal, Harrison, and Speidel were all driven by the same interest in the growth cone.  Although all three men were researching at different times, they laid down stepping stones for each other and provided a basis for the next scientist to build off of and the current understanding of the growth cone has advanced significantly.  Because of their work, we know that growth cones appear in several different ways and voyage at different speeds as they follow their unique pathway.  There are simple follower axons that grow along the path that was set up by a more complex pioneer axon.  Using low light video cameras, scanning laser illumination, and special image software together with the use of fluorescent labels that travel along the neurons axon, the process of outgrowth and innervations can be viewed through time-lapse movies (Sanes, 2012).   
            There is still much research to be done before it is fully known how growth cones work and what triggers cause them to grow the way that they do.  The understanding of this complex process will be extremely useful in creating new treatments for injuries such as spinal cord damage, burns and individuals who need organ transplants because it could result in creating a way to regenerate new tissue for healing.  As an individual who has had to receive bone marrow and will continue to receive bone marrow throughout my lifetime, I find this topic extremely intriguing.  With the continual research on growth cones, a new method of bone marrow regeneration may be discovered and the thought of no longer needed to rely on other people’s bodies is liberating to me. Hopefully the solid foundation laid by Ramon y Cajal, Harrison, and Speidel will provide scientists and physicians a place to continue research in hopes of fully understanding the function and pathways involved in growth cones.    

Sunday, October 23, 2011

The Blind Can See?

While researching, I came across an intriguing article about an elderly woman who, after suffering from years of blindness, began seeing vivid, colorful images.  She was confused as to why she was suddenly seeing things in great detail, and was surprised to find out that she was actually having hallucinations. She was diagnosed with a condition called Charles Bonnet syndrome.  The idea of a blind person suddenly having temporary visions was absolutely astounding to me and I felt the need to know more. 
                Charles Bonnet Syndrome is described as “visual hallucinations of the blind.”  People with the disorder are not actually seeing anything but are instead having hallucinations of a very vivid, colorful, and detailed nature.  The visions are anything from people and animals to inanimate objects and can last anywhere from minutes to hours. Many people are able to control the visions by shutting their eyes or quickly moving their eyes from object to object within the vision.  Charles Bonnet Syndrome is very often accompanied by Diabetes and can occur more often when the individual’s blood sugar is not under control.  Currently, the cause of Charles Bonnet Syndrome is unknown and there is no treatment for the disorder.
                I have many unanswered questions after reading this article. First, is Charles Bonnet Syndrome even related to a brain disorder or does it only occur in individuals with diabetes? I read several articles about the condition and all seemed to have some connection to diabetes, but as the cause is unknown it is hard to pinpoint if diabetes is the underlying cause.  If it is not caused by diabetes, is it similar to schizophrenia and other types of conditions that cause delusions? I feel like there is a lot of research to be done before this syndrome is fully understood, but until then, it is interesting to think that the blind are able to see.    

http://neuro.psychiatryonline.org/cgi/content/full/22/2/247-s.e28

Just sleep on it???

Almost everyone has probably received the advice “just sleep on it.” I myself have been confronted with big decisions where, instead of just making a choice, I say I am going to think about it for a night.  New research is showing that taking your time and “sleeping on it” is actually as ineffective and harmful and making snap decisions.  So, what is the right way to make a tough decision?
A study by Dutch researcher, Dijksterhuis and his colleagues, suggested in their article “Sleep on It” published in a 2006 version of the journal Science, that leaving decisions to the unconscious state was the best way to come up with a solution. However, recent studies are saying that pushing decisions off in order to sleep on it is not an effective way to solve a problem.  Instead, the best way to reach a solution is research…don’t we all just love to hear that.  By researching and coming up with lists of pros and cons, the decision maker can make an informed decision and weigh out all the options, instead of just hoping that an answer will magically appear from the depths of our slumber.  While the unconscious mind does provide relief and escape from often nagging decisions, the break does nothing to help reach a solution.
So, next time you are faced with a tough decision, don’t just sleep it; RESEARCH!! It’s the only way to truly know and understand all your potential options. 
http://www.tricitypsychology.com/complex-decision-dont-sleep-on-it-research/

Sunday, October 9, 2011

Synesthesia

Synesthesia: Mechanisms and Correlations to Autism
Beginning his speech about synesthesia, David Eagelman asked if anyone knew a synesthete.  Since, at the time, I was completely unaware of what a synesthete is, I did not raise my hand.  I did not realize that, for two summers, I worked as a personal care assistant for a synesthete.  It was not until Eagelman started to describe the astonishing and extremely intriguing characteristics of these individuals that it occurred to me that I do in fact know one of these amazing people. I spent day after day with this little boy who, besides being a synesthete, is also autistic. While caring for him, I believed that his ability to tell me in less than five seconds that July 24th, 1962 was a Tuesday was just part of his autism and not a condition known as number-form synesthesia.  After Eagelman’s talk, I began wondering if there is some sort of correlation between autism and synesthesia because I have heard of several other autistic individuals with this similar trait. Through research, I found that fifteen percent of people with autism also experience characteristics of synesthesia (Eagleman) compared with 0.05 percent to one percent of the general adult population (Asher). This statistic seemed quite intriguing and led me to not only study the mechanisms behind synesthesia, but to also find the relationship between synesthesia and autism. 
            The word synesthesia literally means “joined senses,” and individuals with the condition have the capacity to hear colors, taste shapes, and experience other types of sensory blendings that seem nearly impossible for the average person to even imagine. Cross-sensory metaphors like “sharp taste” or “feeling blue” will sometimes be referred to as synesthetic, but true synesthesia is involuntary.  The five characteristics to diagnose a synesthete are: the individual’s actions must be involuntary and automatic, perceptions are spatially extended so that the synesthete often speaks of going a certain place to reach the experience, perceptions are consistent, perceptions are memorable, and synesthesia occurs because of an emotion (Grossenbacher).  Although there are many types of synesthesia, those involving color seem to be the most common with 80.6% to 95% of all synesthetes reporting that their cross-sensory pairings involve colors (Eagelman). Synesthetes are often surprised to discover that other people do perceive sounds, numbers, shapes, and tastes the way that they do and do not find their enhanced senses to be unique (Grossenbacher).
Some of the common forms of synesthesia include grapheme-color, in which the individual has different tints and shades of colors designated to specific letters and numbers, number-form synesthsia, where the synesthete forms a mental map so that all numbers and dates have a designated spot on the map, and personification synesthesia which is when ordered sequences, such as lists and songs, are associated with their certain personality traits.  When a synesthete hears a sound and relates the sound to a certain shade of color, it is referred to as sound-color synesthesia, and with lexical-gustatory synesthesia, the person associates language with certain flavors, so a person’s voice may taste like an apple (Grossenbacher).  Because each part of the brain is specialized to complete a specific task, it is believed that “cross-talk” between areas that are specific for different functions accounts for the wide variety of different synesthesias (Eagleman).
            Although the cause of synesthesia is not completely understood, there are several areas of the brain that definitely seem to contribute to its occurrence. Using functional magnetic resonance imaging (fMRI), it has been revealed that during synesthetic percepts, the brain is activated in the expected areas and if a person associates a flavor with a certain number, the area of the brain that senses taste will experience the stimulus (Spector). 
Neuroimaging studies have also unleashed some of the underlying mechanisms behind synesthesia. The medial areas of the ventral brain pathway are involved in the sorting of visual cues when an individual views an object and is specialized for processing the surface cues that relate to an object’s material properties. Texture and color are two very different characteristics, but both are material properties and there is a significant amount of overlap in the brain areas that process these qualities.  Several of the regions that process texture also deal with color, and there is significant evidence made visible through neuroimaging showing that the “color center” of the brain, also referred to as V4, processes texture as well. Texture and color is only one example of this overlapping, and there are other closely related senses such as the color/sound perceptions that also experience forms of synesthesia (Eagleman).
Another possible cause for synesthesia may be disinhibited feedback.  In normally existing feedback pathways, excitation and inhibition are equal, but in disinhibited feedback, there is a reduction in the amount of inhibition.  If normal feedback is not inhibited, signals from earlier sensory experiences could activate and influence later senses, creating a multi-sensory experience that resembles synesthesia (Spector).
Some forms of synesthesia have also been linked to an area on chromosome 2, which interestingly, is the same area that has been linked to autism and epilepsy.  Because of this occurrence, synesthesia is sometimes reported as a symptom in autism-spectrum disorders, and sensory and perceptual abnormalities are common in individuals with autism.  People with autism spectrum disorders (ASDs) often claim to experience feelings of “sensory-overload” similar to the same feelings that synesthetes have.  Neuropathological studies have shown that individuals with autism have abnormally high levels of connectivity in their brains and alterations in their white matter which could explain the hyperconnectivity that has also been found in the brains of synesthetes (Asher).
There are also several candidate gene mutations present in individuals with synesthesia. A gene called TRB1 induces the transcription of genes regulated by the T-box, including RELN, a gene that is important in the development of the cerebral cortex.  Abnormalities in the TRB1 gene could account for the hyperconnectivity observed in synesthetes.  These connectivity alterations have fascinating implications for synesthesia, in which a lowered excitability threshold, which was discussed earlier in this paper, could result in “cross-talk” between the neurons.  Mutations of TRB1 and RELN have also been linked to individuals with autism which strengthens the correlation between synesthesia and people with autism (Asher).
There is still much research to be done on the amazing, yet extremely obscure topic of synesthesia. Although mechanisms of the condition can be linked to “cross-talking” in the brain, sorting of visual cues, disinhibited feedback, hyperconnectivity, chromosome 2, and gene mutations, there is still not a complete understanding or definitive answer to the actually causes synesthesia.  There is also evidence supporting my own theory at the beginning of my research that shows that synesthesia and autism are indeed linked. 
By understanding synesthesia, there is potential to increase our knowledge of human cognition and perception.  With more understanding of the neural mechanisms behind synesthesia scientists can learn more about cognitive development and neurodevelopmental disorders.  Many of these disorders, such as autism, involve abnormal sensory perception similar to many synesthetes.  With increased understanding of the different forms of synesthsia, we may be armed with the proper information to not only find a treatment for neurodevelopmental disorders, but we may also have the knowledge to prevent them before an individual is even born.  Also, because the perceptions of an individual with synesthesia occur without direct sensory stimulation, by discovering the underlying mechanism behind synesthesia, it may finally be understood how the human brain turns the data it receives through senses into conscious perception, which could finally lead to the discovery of the neural basis of consciousness, a topic that remains unsolved.  There are so many mystifying secrets imbedded in the human brain, and so much more research to be done on a topic that may never be fully understood.  
            The continual research in the field of synesthesia is extremely important.  The knowledge I myself gained from the writing of this paper is immense and not only enlightened me on a subject that I had very little understanding of, but also sparked my interest for more areas of research. I now have a greater appreciation for the quirky comments and incessant talking I endured from the incredibly intelligent little autistic boy I took care of for two summers. 







Works Cited
Grossenbacher, P.G., Lovelace, C.T. (January 2001). Mechanisms of synesthesia: cognitive and
            physiological constraints. Trends Cogn. Sci. 5 (1): 36-41.
Asher, J.E. et. al. (February 2009). A whole-genome scan and fine-mapping linkage study of
            auditory-visual synesthesia reveals evidence of linkage to chromosomes 2q24, 5q33,
            6p12, and 12p12. American Journal of Human Genetics. 84 (2): 279-285.
Spector, F., Maurer, D. (2009). Synesthesia: a new approach to understanding the development
            of perception. Developmental Psychology. 45 (1): 175-189.
Eagleman, D.M., Goodale, M.A., (2009). Why color synesthesia involves more than color.
            Trenda Cogn. Sci. 13 (7): 288-292.